Vestibular migraine: clinical aspects and pathophysiology.
ABSTRACT Vestibular migraine is becoming recognised as a distinct clinical entity that accounts for a high proportion of patients with vestibular symptoms. A temporal overlap between vestibular symptoms, such as vertigo and head-movement intolerance, and migraine symptoms, such as headache, photophobia, and phonophobia, is a requisite diagnostic criterion. Physical examination and laboratory testing are usually normal in vestibular migraine but can be used to rule out other vestibular disorders with overlapping symptoms. The pathophysiology of vestibular migraine is incompletely understood but plausibly could include neuroanatomical pathways to and from central vestibular structures and neurochemical modulation via the locus coeruleus and raphe nuclei. In the absence of controlled trials, treatment options for patients with vestibular migraine largely mirror those for migraine headache.
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ABSTRACT: Vestibular migraine (VM) is a common disorder in which genetic, epigenetic, and environmental factors probably contribute to its development. The pathophysiology of VM is unknown; nevertheless in the last few years, several studies are contributing to understand the neurophysiological pathways involved in VM. The current hypotheses are mostly based on the knowledge of migraine itself. The evidence of trigeminal innervation of the labyrinth vessels and the localization of vasoactive neuropeptides in the perivascular afferent terminals of these trigeminal fibers support the involvement of the trigemino-vascular system. The neurogenic inflammation triggered by activation of the trigeminal-vestibulocochlear reflex, with the subsequent inner ear plasma protein extravasation and the release of inflammatory mediators, can contribute to a sustained activation and sensitization of the trigeminal primary afferent neurons explaining VM symptoms. The reciprocal connections between brainstem vestibular nuclei and the structures that modulate trigeminal nociceptive inputs (rostral ventromedial medulla, ventrolateral periaqueductal gray, locus coeruleus, and nucleus raphe magnus) are critical to understand the pathophysiology of VM. Although cortical spreading depression can affect cortical areas involved in processing vestibular information, functional neuroimaging techniques suggest a dysmodulation in the multimodal sensory integration and processing of vestibular and nociceptive information, resulting from a vestibulo-thalamo-cortical dysfunction, as the pathogenic mechanism underlying VM. The elevated prevalence of VM suggests that multiple functional variants may confer a genetic susceptibility leading to a dysregulation of excitatory-inhibitory balance in brain structures involved in the processing of sensory information, vestibular inputs, and pain. The interactions among several functional and structural neural networks could explain the pathogenic mechanisms of VM.Frontiers in Neurology 02/2015; 6.
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ABSTRACT: Persons with vestibular disorders experience symptoms of dizziness and balance dysfunction, resulting in falls, as well as impairments of daily life. Various interventions provided by physical therapists have been shown to decrease dizziness and improve postural control. In the present review, we will focus on the role of physical therapy in the management of vestibular symptoms in patients with peripheral and central vestibular disorders. Persons with both acute and chronic central and peripheral vestibular disorders improve with vestibular rehabilitation. New interventions during the past 5 years have been designed to enhance recovery from problems with balance and dizziness. Examples include the use of virtual reality, vibrotactile feedback, optokinetic flow, YouTube videos, and innovative methods to change the gain of the vestibulo-ocular reflex (VOR). Patients with central and peripheral vestibular disorders benefit from physical therapy interventions. Advances in physical therapy interventions include new methods to stimulate adaptation of the VOR and the vestibulospinal systems.Current Opinion in Neurology 12/2014; · 5.73 Impact Factor
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ABSTRACT: Vestibular migraine (VM), a common cause of vestibular symptoms within the general pop-ulation, is a disabling and poorly understood form of dizziness. We sought to examine the underlying pathophysiology of VM with three studies, which involved the central synthesis of canal and otolith cues, and present preliminary results from each of these studies: (1) VM patients appear to have reduced motion perception thresholds when canal and otolith signals are modulated in a co-planar manner during roll tilt; (2) percepts of roll tilt appear to develop more slowly in VM patients than in control groups during a centrifugation par-adigm that presents conflicting, orthogonal canal and otolith cues; and (3) eye movement responses appear to be different in VM patients when studied with a post-rotational tilt paradigm, which also presents a canal–otolith conflict, as the shift of the eye's rotational axis was larger in VM and the relationship between the axis shift and tilt suppression of the vestibulo-ocular reflex differed in VM patients relative to control groups. Based on these preliminary perceptual and eye movement results obtained with three different motion paradigms, we present a hypothesis that the integration of canal and otolith signals by the brain is abnormal in VM and that this abnormality could be cerebellar in origin. We provide potential mechanisms that could underlie these observations, and speculate that one of more of these mechanisms contributes to the vestibular symptoms and motion intolerance that are characteristic of the VM syndrome.Frontiers in Neurology 11/2014; 5:233.
www.thelancet.com/neurology Vol 12 July 2013
Vestibular migraine: clinical aspects and pathophysiology
Joseph M Furman, Dawn A Marcus, Carey D Balaban
Vestibular migraine is becoming recognised as a distinct clinical entity that accounts for a high proportion of patients
with vestibular symptoms. A temporal overlap between vestibular symptoms, such as vertigo and head-movement
intolerance, and migraine symptoms, such as headache, photophobia, and phonophobia, is a requisite diagnostic
criterion. Physical examination and laboratory testing are usually normal in vestibular migraine but can be used to
rule out other vestibular disorders with overlapping symptoms. The pathophysiology of vestibular migraine is
incompletely understood but plausibly could include neuroanatomical pathways to and from central vestibular
structures and neurochemical modulation via the locus coeruleus and raphe nuclei. In the absence of controlled
trials, treatment options for patients with vestibular migraine largely mirror those for migraine headache.
Although recurrent vertigo in children was known to be
associated with migraine since Basser’s description in
1964,1 in 1984 Kayan and Hood2 alerted the clinical
community to an important association between
vestibular symptoms and migraine in adults. Since that
time, appreciation of the role of migraine in the dizzy
patient has grown. In fact, although a migrainous
aetiology for vestibular symptoms was previously
unknown or deemed highly speculative, members of the
International Headache Society in collaboration with
members of the Barany Society have published diagnostic
criteria for a disorder called vestibular migraine.3 As
vestibular migraine is rapidly becoming recognised as a
common vestibular disorder, and diagnostic criteria have
been promulgated, the specialty is poised to make
substantial advances in understanding the patho-
physiology of this disorder and improving its
management. In this Review, we provide an update
regarding both the clinical aspects of vestibular migraine
and the neurobiological basis for the disorder. Our
current understanding of vestibular migraine is
rudimentary but continues to evolve. We aim to provide
both clinicians and clinician-scientists with the latest
relevant information regarding this frequently en-
countered disorder and with the latest ideas and basic
science fi ndings germane to the pathophysiology and
rational treatment of vestibular migraine.
Patients frequently present with a combination of
migraine and vestibular symptoms.2 The assessment of
these patients needs to address the association between
these disorders. That is, are the vestibular symptoms
causally related to a migraine subtype; are the vestibular
symptoms and the migrainous symptoms simply a
chance co-occurrence, or is there some more complex
comorbidity association? Currently, the only Inter-
national Headache Society migrainous disorder that
includes vertigo in its classifi cation is basilar-type
migraine, which is characterised by the occurrence of
neurological symptoms originating from the brainstem
or both cerebral hemispheres simul taneously. The
diagnosis of basilar-type migraine might be more
appropriately classifi ed as a type of migraine with aura.4
In two groups of patients with basilar-type migraine,
61–63% reported vertigo as a symptom.5,6 However, few
migraine patients with vestibular symptoms meet criteria
for basilar-type migraine.7 Additionally, although some
patients with migraine have vertigo as a premonitory
symptom, the vertigo cannot often be characterised as an
aura because of its duration or temporal association with
headache. Thus, with present International Headache
Society classifi cation criteria, the vestibular symptoms of
many patients with migraine would be deemed unrelated
to migraine. However, most migraine patients with
vestibular symptoms do not have a recognised
independent vestibular disorder such as Ménière’s
disease, benign paroxysmal positional vertigo, or
vestibular neuritis. As a result, many patients with both
migraine and vestibular symptoms do not have a specifi c
diagnosis to account for their vestibular symptoms. In
response to this defi ciency when reaching an accurate
diagnosis in many migraine patients with vestibular
symptoms, Neuhauser and colleagues8 developed
diagnostic criteria for what is now termed vestibular
migraine, a disorder in which vestibular symptoms are
judged as part of the migrainous disorder itself.
Nearly 1% of the general population meet these criteria,8
which is fi ve to ten times higher than the prevalence of
Neuhauser and colleagues’8 criteria for vestibular
migraine have been reassessed favourably in a recent
long-term follow-up paper.10 A structured diagnostic
interview using the criteria11 has been used in studies of
the clinical features, epidemiology, genetics, patho-
physiology, and treatment of vestibular migraine. The
most recent diagnostic criteria for vestibular migraine, a
refi nement of the 2001 Neuhauser and colleagues
criteria, arose from a working group within the Barany
Society (panel).3 Recently, Cohen and colleagues12
advocated the development of diagnostic criteria by the
International Headache Society to account for the
heterogeneity and natural history of vestibular migraine.
Internationally proposed diagnostic criteria for vestibular
migraine based on those developed by the Barany Society
and the International Headache Society3 will be included
in an appendix of the third edition of the International
Lancet Neurol 2013; 12: 706–15
Department of Otolaryngology
(Prof J M Furman MD,
Prof C D Balaban PhD) and
Department of Anesthesiology
(Prof D A Marcus MD),
University of Pittsburgh,
Pittsburgh, PA 15213, USA
Prof Joseph M Furman,
University of Pittsburgh School
of Medicine, Pittsburgh,
PA 15213, USA
www.thelancet.com/neurology Vol 12 July 2013 707
Classifi cation of Headache Disorders. This appendix will
suggest that vestibular migraine is a new disorder for
which more research is warranted.
Vestibular migraine can be thought of as a migraine
variant with vestibular symptoms or a balance disorder
that includes migraine. Although such a distinction
might seem to have little clinical relevance, because
patients with vestibular migraine can present to either
otolaryngologists or neurologists, patients might receive
diff erent care depending on the type of specialist to
whom they present. A study by Millen and colleagues13
shows that specialists have diff erent views regarding the
manifestations of vestibular migraine. For example,
more neurologists than otolaryngologists believe that
vestibular migraine results from a CNS rather than a
peripheral vestibular abnormality.
Vestibular migraine is more prevalent than other vestibular
disorders.14 Lempert and Neuhauser15 report a lifetime
prevalence of migraine of 16%, a lifetime prevalence of
vertigo of 7%, and a comorbidity of 3·2 %, rather than the
1·1% expected by chance alone. Neuhauser and colleagues16
report that vestibular migraine has a 1-year prevalence of
0·89% and accounts for about 10% of patients seen for
dizziness and about 10% of patients seen for migraine.17
Hsu and colleagues18 report that the 1-year prevalence of
vestibular migraine in women aged 40–54 years is 1%.
For most patients, vestibular migraine is an episodic
disorder; however, the duration of attacks ranges from
seconds to days. Vestibular migraine has a strong female
predominance of up to 5 to 1,11 and vestibular migraine
often begins several years after typical migraine. Some
patients can have a headache-free interval of several years
before onset of vestibular migraine. Vestibular migraine
might begin in place of headache especially in
perimenopausal women.19 Vestibular migraine is more
common in patients without aura than in patients with
aura. The temporal association between the vestibular
symptoms and migrainous symptoms such as headache
is quite variable between patients and the association
might be inconsistent in an individual. Furthermore,
patients might have migraine headache at the same time
as their vestibular symptoms, which include spontaneous
vertigo—ie, an illusory sensation of motion of self or
surround, dizziness induced by head movement,
positional vertigo, or gait instability. Other symptoms can
include visual motion sensitivity and hearing loss, and
migrainous symptoms such
phonophobia. Episodes of vestibular migraine can be
brought about by the same triggers as those for migraine
headache, including menstruation, irregular sleep, stress,
physical exertion, dehydration, food and drinks, and
intense sensory stimulation.17 Quality of life measures are
as photophobia or
generally lower in individuals with vestibular migraine,16
including problems with sleep and depression.20
The physical examination of patients with vestibular
migraine is generally normal between episodes. During
episodes of vestibular migraine, patients usually manifest
a nystagmus that suggests either a central or peripheral
vestibular abnormality.21–23 Non-paroxysmal positional
nystagmus is especially common during attacks of
Physiological fi ndings alone cannot be used to specifi cally
diagnose patients with vestibular migraine because of
their inconsistent pattern and high incidence in patients
with migraine without vestibular complaints.24 However,
physiological testing can be used to help rule out other
vestibular disorders and to establish the extent of vestibular
abnormalities if they exist. Between 10% and 20% of
patients with vestibular migraine have a unilateral
reduction of vestibular function24–26 and many patients have
a directional preponderance.25 Teggi and colleagues27 and
Celebisoy and co-workers26 found that patients with
vestibular migraine had higher postural sway than did
patients without vestibular migraine. Two studies have
documented abnormalities of vestibular-evoked myogenic
potentials in patients with vestibular migraine including
reduced amplitudes either unilaterally or bilaterally.28,29
Several studies have investigated the genetics of
vestibular migraine. Jen30 concluded that vestibular
Panel: Diagnostic criteria for vestibular migraine
Patients need to meet all four of the following criteria:
• At least fi ve episodes with vestibular symptoms* of
moderate or severe intensity† lasting between 5 min and
• Present migraine or previous history of migraine with or
without aura according to the International Classifi cation
of Headache Disorders
• One or more migraine features with at least 50% of the
• Headache with at least two of the following
characteristics: one-sided location, pulsating quality,
moderate or severe pain intensity, aggravation by
routine physical activity
• Photophobia and phonophobia
• Visual aura
• Not explained by another vestibular disorder
*Vestibular symptoms include: spontaneous vertigo, positional vertigo, visually induced
vertigo, head motion-induced vertigo, head motion-induced dizziness with nausea.
†Vertigo is rated as moderate if vertigo interferes with but does not prohibit daily
activities and as severe if daily activities cannot be continued. Modifi ed from Lempert and
colleagues,3 by permission of IOS Press.
www.thelancet.com/neurology Vol 12 July 2013
migraine might be monogenic and heterogeneous. Von
Brevern and colleagues31 found no evidence of an
association between calcium and sodium channel genes
linked to familial hemiplegic migraine and episodic
ataxia type 2 and vestibular migraine. Lee and colleagues32
found a region on chromosome 11q that is common in
females in a family with vestibular migraine. Bahmad
and colleagues33 located a 12·0 MB interval on
chromosome 5q35 that contained a disease gene for
familial vestibular migraine. The pathophysiology of this
disease gene remains unknown.
Several balance disorders are related to vestibular
migraine. Ménière’s disease, benign paroxysmal positional
vertigo, and anxiety are more common in patients with
vestibular migraine than would be expected by chance
alone. The basis for this high comorbidity remains
uncertain but might relate to overlaps between the clinical
characteristics of these disorders and those of vestibular
migraine, and because vertigo can serve as a migraine
trigger.34 Ménière’s disease and vestibular migraine
overlap extensively in their clinical manifestations, and in
some patients it might be impossible to establish whether
they have one or both disorders. Patients with Ménière’s
disease are twice as likely to have migraine as individuals
without Ménière’s disease,35 and patients with migraine
are more likely to have an earlier onset and bilateral
hearing loss with Ménière’s disease.36 Cha and colleagues37
discovered a frequent association among episodic vertigo,
migraine, and Ménière’s disease in closely related
individuals. Like patients with Ménière’s disease, patients
with benign paroxysmal positional vertigo are more likely
to have migraine than patients without benign paroxysmal
positional vertigo.38 Patients with migraine are also more
likely to have benign paroxysmal positional vertigo than
individuals without migraine.39 The highly common
fi nding of persistent rather than paroxysmal positional
nystagmus in patients with vestibular migraine
complicates this association.22
especially anxiety and depression, is especially common
in patients with vestibular migraine.40,41 In a prospective
study of psychiatric illness in vertigo syndromes, only
patients with vestibular migraine had increased rates of
psychiatric illness 1 year after establishing a vestibular
diagnosis.42 Patients with vestibular migraine reported
more vertigo, more somatic anxiety and autonomic
arousal, and more vertigo-induced handicap than did
other patients with vertigo.43 Although not strictly a
balance disorder, motion sickness susceptibility is more
common in patients with migraine in general and patients
with vestibular migraine in particular.44,45
Treatment options for patients with vestibular migraine
include reduction of triggers, pharmacotherapy, physical
therapy, and mitigation of comorbidities. No dedicated
evidence base is available and no randomised controlled
trials for the treatment of vestibular migraine exist, mainly
because of the hitherto lack of diagnostic criteria. Instead,
treatments are based on those for migraine headache or
are anecdotal. Avoidance of migraine triggers should
always be the fi rst avenue of treatment. Pharmacotherapy
can be abortive, symptomatic for episodes, and
prophylactic. Although diagnostic criteria for vestibular
migraine are now available, no randomised treatment
studies have been done, except for a small inconclusive
study of zolmitriptan as an abortive agent.46 Symptomatic
treatment for acute episodes of vestibular migraine is
similar to treatment for acute vertigo with peripheral
vestibular causes, including vestibular suppressants such
as promethazine, dimenhydrinate, and meclozine.
Physical therapy has been reported to improve imbalance
in patients with vestibular migraine in an uncontrolled
study.47 In general, the scientifi c literature suggests that
drugs effi cacious for prophylaxis of migraine headache
are also appropriate for prophylaxis of vestibular
migraine.48 On the basis of mainly opinion, and not on
controlled studies, researchers have advocated β-blockers
such as propranolol or metoprolol; antidepressants such
as amitriptyline, nortriptyline, fl uoxetine, sertraline, or
paroxetine; calcium-channel blockers such as verapamil
or diltiazem; anticonvulsants such as valproate,
topiramate, or lamotrigine; and carbonic anhydrase
inhibitors such as acetazolamide.49–51
Proposed neurobiological bases
Present hypotheses of migraine mechanisms are based
on results of combined genetic, in-vitro cell biological,
animal model, and clinical studies in human beings.52–58
This well developed published work provides a conceptual
framework for understanding vestibular migraine as a
variant produced by the convergence of vestibular
information within migraine circuits; therefore, we
provide a framework for further development of our
understanding of vestibular migraine.
Vasculature, migraine mechanisms, and the inner ear
The large overlap between migraine pathways and
vestibular pathways41,59–61 is consistent with the view that
vestibular migraine is a migraine variant with vestibular
manifestations. Specifi cally, the vascular, neurogenic
infl ammation, and central neural mechanisms that have
been implicated as peripheral and central triggers of
migraine52–56 are all present in central vestibular pathways
and the inner ear. For example, the trigeminocerebro-
vascular system57 provided a focus to investigate the link
between vascular responsiveness and pain as a
physiological consequence of activation of trigeminal
ganglion innervation of cerebral and meningeal
vasculature. The trigeminovascular system also innervates
the blood supply of the inner ear.62,63 Iadecola58 provided a
more integrative context for migraine mechanisms,
suggesting that a neocortical, extracellular release of
www.thelancet.com/neurology Vol 12 July 2013 709
signals (eg, K+, H+, arachidonic acid, and nitric oxide)
during cortical spreading depression would activate
trigeminal aff erents on cranial blood vessels, which would
elicit a trigeminovascular refl ex-mediated vasodilation in
the meninges via a parasympathetic relay in the
sphenopalatine ganglion. Simultaneously, as described by
Moskowitz,54 a sterile infl ammatory response is elicited
from meningeal vessels by peptide secretion from axon
collaterals of the trigeminal ganglion cells.
Parallel events have been observed in the inner ear of
animals.64,65 The trigeminal innervation of the inner ear
seems to be a component of trigeminal innervation of
other intracerebral blood vessels,62,63,66 and similar eff ects
on inner ear blood perfusion have been seen in animal
experiments.67–70 Because the trigeminovascular refl ex
innervation of the inner ear is one component of the
trigeminovascular refl ex system, the innervation is a
potential site of action for abortive eff ects of triptans,
ergots, and calcitonin gene-related peptide antagonists on
peripheral triggers in patients with vestibular migraine.
Migraine prophylaxis drugs, such as acetazolamide and
topiramate, have the potential to support endolymph
homoeostasis by inhibition of carbonic anhydrase in the
stria vascularis and supporting cells of the sensory
epithelia.71,72 The fact that spiral and vestibular ganglion
cells in rodents and primates express the main serotonin
receptor targets of the
(5-hydroxytryptamine [5-HT]1A, 5-HT1B, 5-HT1D, and 5-HT1F
receptors) is interesting because their binding affi nities
are within the clinical dose-related plasma concentrations
of the drugs.60,73–75 Hence, actions of ganglion cells might
partly explain the effi cacy of these agents in vestibular
migraine. Finally, the eff ects of non-steroidal anti-
infl ammatory drugs might include a blunting of both the
infl ammation and extravasation
triptans and ergots
Integrative migraine mechanisms and vestibular
pathways: translational rules from basic research
Because vasodilation is neither necessary nor suffi cient
for perception of headache pain,56–58,76 migraine headache
pain is attributed mainly to central processing of
trigeminal aff erent activation in ascending thala mocortical
pathways.53,56,58 Specifi cally, Ho and colleagues53 expanded
the idea of the migraine circuit from strictly trigeminal
pathways for vascular regulation and pain perception to a
framework that includes circuits for processing triggers
and premonitory symptoms. External trigger circuits were
proposed to include visual, auditory, somatosensory, and
chemical (olfactory and gustatory) sensory pathways, and
contributions from vascular phenomena. Internal triggers
include hormonal fl uctuations and stress.77 Both internal
and external triggers involve structures such as the
hypothalamus and amygdala, which show altered activity
associated with migraine in functional imaging studies,78–82
and contain a dense calcitonin gene-related peptide-
positive axon plexus among scattered positive neurons in
animals and human beings.83–86 The central constituents
of the migraine circuit include components of central
vestibular pathways. For example, the regions aff ected by
vestibular stimulation in human functional imaging
studies include those involved in migraine and pain
perception, such as the posterior insula, anterior insula,
orbitofrontal cortex, and the posterior and anterior
cingulate gyri.87–93 Additionally, because the caudal
parabrachial nucleus receives
nociceptive94–96 and vestibular inputs in rodents and
primates,97–100 the related pathways might contribute to
symptoms of vestibular migraine, including motion
sensitivity and its interaction with trigeminal pain in
migraine patients.97–104 Furthermore, the high expression
of stress-response receptors in the amygdala and
hypothalamus105 suggests a role of stress interactions with
development of migraine signs and symptoms.77
Vestibular processing and migraine circuits
Vestibular migraine is an example of the integral overlap
between vestibular pathways and migraine circuit
triggers and central mechanisms for premonitory
symptom generation (fi gure). Information transmitted
by peripheral vestibular sensory organs and the vestibular
nerve to the medulla and pons is an external trigger
within the migraine circuit construct proposed by Ho
and colleagues.53 Hence, the abortive eff ects of drugs in
the inner ear (eg, triptans, ergots, calcitonin gene-related
peptide antagonists, non-steroidal anti-infl ammatory
drugs, lamotrigine, calcium-channel blockers, and
topiramate) can attenuate a peripheral trigger specifi c for
vestibular migraine, and aff ect a central migraine circuit.
Similarly, the perceptual and sensorimotor consequences
of unilateral or bilateral disruptions of peripheral
vestibular function constitute internal triggers of
vestibular migraine within their framework because the
migraine circuit overlaps extensively with the vestibular-
related pathways that have been discussed in the context
of comorbidity of balance disorders, migraine, and
anxiety disorders.59–61 The central vestibular pathways that
overlap with internal trigger mechanisms for the
migraine circuit have been parsed conceptually into a
interoceptive component, which are each modulated by
the dorsal raphe nucleus and locus coeruleus (fi gure).
perceptual responses to vestibular, visual, proprioceptive,
and somatosensory aff erent inputs. The domain also
includes pathways related to premonitory symptoms
associated with balance control, such as circuits involving
the ventral lateral prefrontal cortex, orbitofrontal cortex,
and the ventral aspect of the cingulate cortex that
communicate with the interoceptive domain for regulation
of aff ect. The sensorimotor performance component
generates somatic and visceral motor responses to aff erent
and component, an
that produce networks
www.thelancet.com/neurology Vol 12 July 2013
sensory information. The balance-related sensorimotor
component includes brainstem pathways that generate
somatic (eg, vestibulo-ocular and vestibulospinal refl exes)
and visceral (vestibulosympathetic and vestibulopara sym-
pathetic)107,108 motor responses.
sensorimotor responses are modulated by the cere-
bellum,107,109 which has been activated in human imaging
studies during migraine attacks81,110,111 and shows prominent
expression of calcitonin gene-related peptide receptors in
association with Purkinje cells in animals.112 The trigeminal
nociceptive sensorimotor pathways include aff erent
sensory thalamocortical pathways, the periaqueductal grey,
and the trigeminovascular refl ex circuit. More importantly,
neuroanatomical tracing studies have shown extensive
interconnections among the spinal trigeminal nucleus,
vestibular nuclei, and the solitary nucleus100,113–117 and that
small cervical dorsal root ganglion cells contribute to
primary aff erent projections to vestibular nuclei.118,119 These
observations clearly show that the vestibular nuclei
contribute to the migraine circuit at the level of the caudal
Interoceptive circuits assess information about present
sensory and motor processes relative to the physiological
status of the individual,120 and translate this information
into subjective awareness and feelings (often termed the
sentient self).121 Interoceptive circuits for vestibular,
visceral sensory, and nociceptive information include a
network that contains the parabrachial nucleus, central
amygdaloid nucleus, and bed nucleus of the stria
terminalis, several posterior thalamic intralaminar nuclei,
the hypothalamus, and the insular cortex. Neuroanatomical
studies have shown that this network is notable for its
large concentration of calcitonin gene-related peptide
immunoreactive neurons,84,122–125 which include regions
related to visceral, vestibular, and nociceptive pathways
in the rostrodorsal and caudoventral parabrachial
intralaminar nuclei including the subparafascicular
nucleus84,129 and periventricular
hypothalamus. These cells give rise to dense calcitonin
gene-related peptide-immunopositive terminal fi elds in
the insular cortex, central amygdaloid nucleus, bed
nucleus of the stria terminalis, and the amygdalo-strial
transition region.84 This strong co-localisation of
calcitonin gene-related peptide with central interoceptive
pathways raises the possibility that central calcitonin
gene-related peptide antagonism is a strategy to both
alter the interpretation of premonitory sensory activity as
a symptom and interrupt the progression of external and
internal trigger activity.
The closely connected network between the locus
coeruleus and dorsal raphe nucleus is a likely target for
calcitonin gene-related peptide antagonists and triptans
in vestibular migraine (fi gure). This network has the
potential to modulate vestibular migraine-associated
premonitory symptoms and triggers of vestibular
migraine (eg, stress and pain perception) through
widespread eff erent projections to central migraine and
vestibular circuits. The locus coeruleus and the dorsal
raphe nucleus have long been included as modulators of
both central migraine circuits52,56 and vestibular
sensorimotor130–134 and interoceptive circuits.59–61 Locus
coeruleus unit activity in rats and monkeys increases with
exposure to novel or imperative sensory stimuli,
particularly during reorientation of attention in contexts
associated with stress or anxiety.135–137 A large proportion of
locus coeruleus neurons are immunoreactive for
calcitonin gene-related peptide in mammals (including
human beings)84,125,138 and express the stress response-
related corticotropin-releasing hormone, glucocorticoid,
and mineralocorticoid receptors.105 The dorsal raphe
nucleus neurons do not show appreciable calcitonin
gene-related peptide expression but do express
corticotrophin-releasing hormone and mineralocorticoid
regions of the
Figure: Vestibular migraine pathways
Pathways related to sensorimotor performance, interoceptive, and cognitive-behavioural domains within migraine circuits are shown diagrammatically. The boxes
that represent brainstem sensorimotor structures include parallels in peripheral neurochemical organisation between vestibular pathways and migraine
Trigeminal pain pathways
Meningeal, brain, and
Medulla and pons
• Eye movement
• Head movement
• Postural changes
Perceptions and sensations
Midbrain, thalamus, and forebrain
Dorsal raphe nucleus
www.thelancet.com/neurology Vol 12 July 2013 711
receptors highly.105 Raphe neurons and their targets also
express 5-HT1B and 5-HT1D receptors,139,140 which provide
both presynaptic and postsynaptic targets for triptans.
Activity of the dorsal raphe nucleus seems to be associated
with the selection of a behavioural strategy to either act or
orient and gather more information. Activation of the
dorsal raphe nucleus in rats and monkeys accompanies
facilitated motor activity, inhibited sensory information
processing, and concomitant expression of hormonal and
neuroendocrine activity.141 During orienting responses,
reduced activity of these neurons occurs in conjunction
with motor activity disfacilitation and sensory processing
disinhibition. Hence, the interplay between the locus
coeruleus and dorsal raphe nucleus might modulate
perceptual and trigger-related activity in migraine circuits.
Cav2.1 channels and the sodium–potassium ATPase α2
In view of the many components of the migraine and
vestibular migraine circuits, it is not surprising that
identifi cation of one major susceptibility locus has been
elusive in genetic linkage studies.30,31 However, some
candidate mutations from family association studies aff ect
molecules in the inner ear (peripheral trigger mechanisms)
and the brain. For example, functional mutations of a
neuronal voltage-gated calcium channel (Cav2.1) in
familial hemiplegic migraine type 1 and the glial catalytic
α2 subunit of sodium–potassium ATPase (NaKA α2) in
familial hemiplegic migraine type 2 have been discussed
in the framework of neuron-glial-vascular contributions
(neurovascular unit142,143) to cortical spreading depression.144
However, the Cav2.1 (P/Q type) channels have many
potential roles in vestibular migraine. Experiments in
animals show that these channels are mediators of the
trigeminovascular refl ex145 and they can modulate
transmission at dural trigeminocervical aff erent relays in
the spinal cord.146 Additionally, Cav2.1 channels help
regulate calcitonin gene-related peptide release from
neuronal processes in the dura, trigeminal ganglion, and
the spinal trigeminal nucleus.147 The same eff ect is likely
in the inner ear trigeminovascular terminals. Other
mutations of Cav2.1 are associated with vertigo in episodic
ataxia type 5 (CACNB4 mutation) or vertigo plus migraine
in episodic ataxia type 2 (CACNA1A mutation).30 Reduced
otolithocular function is also associated with CACNA1A
mutations in patients with episodic ataxia type 2 and
spinocerebellar ataxia type 6.30 The trigeminal ganglion,148
vestibular ganglion,149 and spiral ganglion150 express Cav2.1
mRNA in rodents, suggesting that mutations can
potentially aff ect both the fi fth and eighth cranial nerves.
Immunoreactivity for NaKA α2, on the other hand, is
associated with fi brocytes below vestibular sensory
epithelia and in the cochlea.72,151 Hence, the antimigraine
actions of the butterbur root sesquiterpenes S-petasin, iso-
S-petasin, and eudesmol might show preferential actions
as use-dependent antagonists of the Cav2.1 channel152 in
vestibular ganglion cells. A similar mechanism of action
is plausible for lamotrigine, calcium-channel blockers,
and topiramate153 in the attenuation of peripheral trigger
susceptibility in vestibular migraine.
Conclusions and future directions
Vestibular migraine is becoming recognised as a highly
prevalent vestibular disorder that is a subtype of migraine.
Recently developed diagnostic criteria have helped clinical
research, allowing a more complete understanding of the
clinical aspects of vestibular migraine. The challenge now
is to better understand the pathophysiology of vestibular
migraine from both a clinical and basic science
perspective to enable improved rational management of
this disorder. Recent studies of vestibular psychophysics154
and motion sickness susceptibility155–157 in vestibular
migraine are yielding exciting new insights. An expanded
view of the migraine circuit motivates basic science
studies of the individual and interactive roles of vestibular
and nociceptive mechanisms in vestibular migraine. For
example, studies of the role of inner ear trigeminovascular
refl exes in blood fl ow regulation, endolymph-perilymph
homoeostasis, vestibular transduction, and vestibular
nerve function are needed to develop rules for
understanding the diff erent eff ects of drugs on the
vestibular symptoms and headache. Additionally, basic
studies are needed to elucidate neuronal processing
interactions between nociceptive
information processing, interactions of nociceptive and
vestibular processing with stress-related receptor
mechanisms—eg, arginine vasopressin, corticotrophin-
releasing hormone, glucocorticoid and mineralocorticoid
receptors105 in migraine circuits—and the eff ects of
antimigraine medications on vestibular nerve and
vestibular nucleus activity. Finally, in view of the parallel
neurochemical organisation of pain and vestibular
pathways, it will be fruitful to investigate the common
genetic bases for vestibular migraine, craniofacial pain158
and interactions between stress and pain,159 including
pharmacogenetic features that might aff ect drug
effi cacy.160 These studies will provide essential new
knowledge to guide controlled treatment trials for
Search strategy and selection criteria
We searched Medline for articles in English published
between Jan 1, 1980, and Dec 31, 2012, with the search
words: “migraine”, “dizziness”, “vertigo”, “vestibular”,
“balance”, and “headache”. Terms were expanded using the
‘exp’ (explode) function and the Boolean ‘AND’ function was
used to select subsets. Studies of human beings and animals
were included. Both original research and review articles were
included. Additional citations were obtained by searching for
additional articles by fi rst authors of articles identifi ed
through the primary search and by reviewing citation lists
within retrieved papers.
www.thelancet.com/neurology Vol 12 July 2013
All authors contributed equally in literature searches, writing, and
creation of fi gures.
Confl icts of interest
We declare that we have no confl icts of interest.
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